Shielding Cancer Cells from Damage

An alternative form of an enzyme involved in the glucose metabolism pathway protects cancer cells from oxidative stress.

By Tia Ghose | November 4, 2011

Lung cancer cellsWIKIMEDIA COMMONS

By activating an enzyme involved in the breakdown of glucose, researchers were able to slow the growth of lung cancer cells and increase the harm inflicted by reactive oxygen species (ROS)—byproducts of normal metabolism that can cause damage to the cell in high concentrations. The findings, published Thursday (November 3) in Science Express, could one day be used to make cancer cells more susceptible to cancer treatments and minimize tumor growth.

“It’s a beautiful paper, very elegant,” said cancer biologist Karen Vousden of the Beatson Institute for Cancer Research in Glasgow, who was not involved in the study. The study shows how tumors normally cope so well with increased oxidative stress and provides an avenue to turn that mechanism against the cancer, she said.

Scientists have long known that cancer cells tend to have an alternative form of the enzyme pyruvate kinase M1 (PKM1), which is part of the glycolysis pathway that breaks glucose down into pyruvate and ATP. Unlike PKM1, whose activity levels are fixed, PKM2 activity can be up- or downregulated, and the alternative form of the enzyme seems to be important in helping tumor cells grow, Vousden said.

Scientists have also been intrigued by the fact that cancer cells can avoid the damage to key cellular components normally sustained as a result of high levels of ROS, said lead author of the study Dimitrios Anastasiou, a cancer biochemist at Harvard Medical School. Cancer cells produce more ROS, yet somehow avoid the usual consequences. Previous work suggested that the PKM2 pathway may play a role in this regulation of oxidative damage.

To understand how, Anastasiou and his colleagues treated lung cancer cell lines with oxidizing agents that increased ROS levels and oxidized PKM2, and found that the cells showed lowered PKM2 activity. When they added reducing agents, on the other hand, which lower ROS levels and reverse the oxidation of PKM2, the enzyme’s activity rebounded, suggesting that PKM2 acted as a sensor for ROS.

Next they created a mutant form of PKM2 that stayed “on,” like PKM1, even as levels of ROS increased. Cancer cells with the mutant form of PKM2 sustained more damage than control cancer lines, suggesting that cancer cell’s ability to lower PKM2 activity in response to high ROS play a key role in buffering cells from damage. When they dug further, they found that lowering PKM2 activity helped cancer cells survive by allowing the regeneration of glutathione, a molecule that neutralizes ROS.

“The icing on the cake is that when we took the cells that expressed the oxidative mutant of PKM2, [implanted them into mice], and asked how well they grew, cells [with] mutant forms grew smaller tumors than the wild-type counterparts,” Anastasiou said.

The findings suggest that researchers may one day be able to turn on PKM2 to make the cancer cells more vulnerable to cancer-killing therapies such as chemotherapy or radiation, he added.

“I think the obvious question is: is it possible to use mechanisms that might inappropriately activate PKM2?” Vousden said. “If you can activate it, make it behave like PKM1, would that be a useful therapeutic?”